Metabolic Dysregulation after Neutron Exposures Expected from an Improvised Nuclear Device

Abstract

The increased threat of terrorism across the globe has raised fears that certain groups will acquire and use radioactive materials to inflict maximum damage. In the event that an improvised nuclear device (IND) is detonated, a potentially large population of victims will require assessment for radiation exposure. While photons will contribute to a major portion of the dose, neutrons may be responsible for the severity of the biologic effects and cellular responses. We investigated differences in response between these two radiation types by using metabolomics and lipidomics to identify biomarkers in urine and blood of wild-type C57BL/6 male mice. Identification of metabolites was based on a 1 Gy dose of radiation. Compared to X rays, a neutron spectrum similar to that encountered in Hiroshima at 1–1.5 km from the epicenter induced a severe metabolic dysregulation, with perturbations in amino acid metabolism and fatty acid β-oxidation being the predominant ones. Urinary metabolites were able to discriminate between neutron and X rays on day 1 as well as day 7 postirradiation, while serum markers showed such discrimination only on day 1. Free fatty acids from omega-6 and omega-3 pathways were also decreased with 1 Gy of neutrons, implicating cell membrane dysfunction and impaired phospholipid metabolism, which should otherwise lead to release of those molecules in circulation. While a precise relative biological effectiveness value could not be calculated from this study, the results are consistent with other published studies showing higher levels of damage from neutrons, demonstrated here by increased metabolic dysregulation. Metabolomics can therefore aid in identifying global perturbations in blood and urine, and effectively distinguishing between neutron and photon exposures.

Identification of differentially expressed genes and pathways in mice exposed to mixed field neutron/photon radiation

“…In addition, we identified pathways related to amino acid and fatty acid oxidation to be among the significantly underrepresented pathways in the 83% neutron exposure. This finding is in agreement with recently published metabolomics data that compared x-rays to neutron radiation and found that neutrons induced a severe metabolic dysregulation, with perturbations predominantly in amino acid metabolism and fatty acid β-oxidation [ 26 ].…”

Metabolomics in Radiation Biodosimetry: Current Approaches and Advances

“…Blood is one of the most commonly used biofluids for any sort of testing, and is an obvious choice to investigate for metabolites that may assist in dose reconstruction, injury diagnosis, and prognosis. Indeed, blood metabolomic markers may be able to distinguish the type of radiation one is exposed to, as was found when mice were exposed to X-ray vs. neutron radiation [36]; or determine specific organ injury, as Jones et al found when studying small intestine tissue metabolites compared to plasma metabolites of mice exposed to TBI [114]. Importantly, some metabolite signatures, including increases in polyunsaturated fatty acid-containing lipids, have been consistently found across mice [115,116], NHPs [26,117], and humans [118], over a range of radiation doses.…”

“…In the case of both sources, changes in metabolites such as citrulline, citric acid, creatine, taurine, carnitine, xanthine, creatinine, hypoxanthine, uric acid, and threonine were consistently observed ( Table 2). Using a neutron source that simulates an exposure similar to that in Hiroshima at 1-1.5 km from the epicenter, investigators demonstrated a severe metabolic dysregulation, with perturbations in amino acid metabolism and fatty acid β-oxidation in irradiated mice [36]. Urinary metabolites were able to discriminate between neutron and X-rays on day 1, as well as day 7 post-irradiation.…”

“…A wide variety of metabolic pathways can be impacted by radiation, as seen in the urine, with changes in biomarkers reflecting damage or changes to the microbiome, urea cycle, as well as amino acid, protein, fatty acid, and hormone metabolism across rodents [123,124], NHPs [125][126][127], and humans [22]. Curiously, Laiakis et al found that metabolic markers in mouse urine could distinguish between lipopolysaccharide (LPS)-induced inflammation and radiation-induced inflammation [128], even different types of radiation were distinguishable in these samples [24,36]. Some urine metabolomic biomarkers like creatinine could even be used to differentiate sub-syndromes or specific organ injury, for example, creatinine levels can indicate kidney damage at high dose rates in NHPs [129].…”

New High Throughput Approaches to Detect Partial-body and Neutron Exposures on an Individual Basis

“…Due to the high relative biological effectiveness of neutrons for causing cytogenetic damage [9][10][11] , the neutron dose contributes roughly 4 times the damage of an equivalent photon dose. Consequently, these neutron components are likely to have a profound impact on disease type and progression [12][13][14][15] . It is also likely that different countermeasures will be required for neutroninduced disease and photon-induced exposure 16 Significance of partial body exposures A significant proportion of individuals exposed indoors to the initial blast from an IND will be exposed non-homogeneously, to a partial body exposure, due to shielding by objects and building materials 7 .…”